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Hereditary angioedema (HAE) has been recognized for almost 150 years. The newest form of HAE, where C1 inhibitor levels are normal (HAE-nC1INH), was first described in 2000. Over the last two decades, new types of apparent non-mast cell-mediated angioedema with normal quantity and activity of C1INH have been described, in some cases with proven genetic pathogenic variants that co-segregate with angioedema expression within families. Like HAE due to C1INH deficiency, HAE-nC1INH patients are at risk of serious morbidity and mortality. Therefore, proactive management and treatment of HAE-nC1INH patients after an expert physician diagnosis is critically important. The underlying pathophysiology responsible for the angioedema has also been clarified in some of the HAE-nC1INH types. While several clinical guidelines and practice parameters including HAE-nC1INH have been published, we have made substantial progress in our understanding encompassing diagnostic criteria, pathophysiology, and treatment outcomes. HAE International (HAEi) and the US HAE Association (HAEA) convened a symposium of global HAE-nC1INH experts to synthesize our current knowledge in the area. Given the paucity of high-level evidence in HAE-nC1INH, all recommendations are based on expert opinion. This review and expert opinion on the best practice approach to diagnosing and treating HAE-nC1INH will support physicians to better manage patients with HAE-nC1INH., Competing Interests: Declarations. Ethics Approval: Not applicable for this literature review. Competing Interests: B.L.Z has served as a consultant for CSL Behring, KalVista, and BioCryst, on the DMSB for CSL Behring and BioMarin, and has had a laboratory service agreement with Ionis. K.B. reports no conflicts in relation to this manuscript. L.B. has consulted/served as speaker for, engaged in research and educational projects with or accepted travel grants from the following companies: BioCryst, CSL Behring, Takeda, Novartis, GSK, Blueprint, Kalvista, Pharvaris. S.C.C. has served on medical advisory boards for BioCryst, KalVista, and CSL Behring. She is a member of the Medical Advisory Board of the US HAEA. H.F. has received speaker fee and travel grants from CSL Behring, Pharming, Takeda, KalVista, and Pharvaris and served as an advisor/consultant for these companies and for Astria, BioCryst, Intellia, Ionis, and ONO Pharmaceutical. A.E.G. reports no conflicts in relation to this manuscript. A.S.G. receives a productivity grant from National Council of Research (CNPq) and a grant from researcher initiative from Shire/Takeda. A.S.G. reports speaking and/or consultancy fees from Catalyst, CSL Behring, Exeltis, KalVista, Multicare, Pharvaris, Pint-pharma, and Takeda. A.K. reports no conflicts in relation to this manuscript. A.L.L. reports conference travel support and speaking fees from Takeda and CSL Behring. M.Ml. reports honoraria or consultation fees from Astria, BioCryst, CSL Behring, Intellia, KalVista, Pharvaris, Shire/Takeda. M.A.R. has served as a research investigator for BioCryst, BioMarin, CSL Behring, Ionis, KalVista, Pharvaris, Takeda and a consultant for Astria, BioCryst, BioMarin, Celldex, CSL Behring, Cycle Pharma, Grifols, Intellia, Ionis, KalVista, Pfizer, Pharming, Pharvaris, Sanofi-Regeneron, Takeda. A.A. reports conference travel support and/or honoraria from BioCryst, CSL Behring, Intellia, and Takeda, and clinical trial support from Astria, CSL Behring, Ionis, KalVista, Octapharma, Pharvaris, and Takeda, outside of the submitted work. A.B. reports research funding from Ionis, Astria, and Intellia, and advisory boards with CSL Behring, Ionis, Pharvaris, Intellia, KalVista, Astria, Takeda. S.B. reports speaker and/or advisor fees from Astria, BioCryst, CSL Behring, Ionis, KalVista Pharmaceuticals, Pharvaris, and Takeda, and research funding from CSL Behring and Takeda. Chair of the Canadian Hereditary Angioedema Network. I.B-G. is or recently was a speaker, advisor, engaged in research and educational projects, and/or received research and consultancy grants from Takeda, CSL Behring, Pharming, KalVista, Pharvaris, and BioCryst. M.B. reports conference travel support and research/advisory fees from Takeda, KalVista, and CSL Behring. H.B.B. reports no conflicts in relation to this manuscript. T.C. is or recently was a speaker, advisor, engaged in research and educational projects, received research grants and/or received funding to attend conferences and educational events from Astria, BioCryst, CSL Behring, IONIS, KalVista, Novartis, Otsuka, Pharming, Pharvaris, and Takeda. She is a researcher in the Hospital La Paz Institute for Health Research (IdiPAZ) program for promoting research activities. M.C. received grant research support and/or speaker/consultancy fees from BioCryst, CSL Behring, KalVista, Novartis, Pharming, Pharvaris, Sanofi, Shire-Takeda, and SOBI. A.J.C. reports no conflicts in relation to this manuscript. D.M.C reports speaking and/or consultancy fees from Astria, BioCryst, CSL Behring, Intellia, Ionis, KalVista, Pharming, Pharvaris, and Takeda. D.C. reports no conflicts in relation to this manuscript. C.D. reports no conflicts in relation to this manuscript. A.F. has received honoraria from CSL Behring, Takeda and Torii, and a consulting fee from KalVista. M.H. has received speaker/consultancy fees for BioCryst, CSL Behring, KalVista, Pharvaris, Takeda, and Torii. C.H.K. reports speaking and/or consultancy fees from CSL Behring, Takeda, BioCryst, KalVista, Pharvaris, and Intellia, outside of the submitted work. P.H.L. reports speaking and/or consultancy fees from CSL Behring, KalVista, Pharvaris, and Takeda, outside of the submitted work. H.L. has collaborated in research and educational projects with, served as a speaker or advisor for, or received educational support from the following companies: CSL Behring, Intellia, KalVista, Pharvaris, Takeda. J.P. reports educational grant support from Takeda and speaking or advisory board fees from Astria, BioCryst, CSL Behring, KalVista, Pharvaris, and Takeda. F.P. reports speaking and/or consultancy fees from CSL Behring, Pharvaris, and Takeda. A.R. reports advisory boards and consultancy from BioCryst, CSL Behring, Ionis, Pharming, Pharvaris, and Takeda and received speaker’s honoraria from BioCryst, CSL Behring, and Takeda. Received research funding from BioCryst, CSL Behring, Ionis, Pharvaris, Shulov, and Takeda (formerly: Shire). B.R. reports conference travel support from CSL Behring, Octapharma, Takeda, and clinical trial support from CSL Behring. C.N.S. reports no conflicts in relation to this manuscript. A.Z. received speaker/consultancy fees from Astria, BioCryst, CSL Behring, KalVista, Otsuka, Pharming, Pharvaris, and Takeda. M.Mr. reports grants or speaker/advisor fees from Astria, BioCryst, CSL Behring, KalVista, Pharvaris and Takeda., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Biological apatite mineral is highly substituted with carbonate (CO 3 2- ). CO 3 2- can exchange for either phosphate, known as B-type, or hydroxyl groups, known as A-type. Although the former has been extensively studied, A-type CO 3 2- into the apatite structure caused the predicted expansion of the a-axis and contraction of the c-axis in the unit cell. This was accompanied by a significant modification in the atomic order, especially along the a-axis plane, and crystallite size. A combination of in situ loading with synchrotron X-ray Diffraction and Density Functional Theory showed that increasing A-type CO 3 2- apatites with biologically relevant levels of CO 3 2- (1.7-5.8 wt%) were prepared and characterized. The addition of A-type CO 3 2- into the apatite structure caused the predicted expansion of the a-axis and contraction of the c-axis in the unit cell. This was accompanied by a significant modification in the atomic order, especially along the a-axis plane, and crystallite size. A combination of in situ loading with synchrotron X-ray Diffraction and Density Functional Theory showed that increasing A-type CO 3 2- substitutions also reduced the bulk and elastic moduli of the crystals. These results show that although A-type CO 3 2- may inhibit lattice changes caused by B-type CO 3 2- , A-type CO 3 2- enhances the reduction in crystal order and mineral stiffness. These results help us to identify the possible contributions of A-type CO 3 2- substitutions in biological apatites that contain both A- and B-type CO 3 2- . In addition, this implies that the stiffness of bioapatite may change with increasing A-type CO 3 2- substitutions, potentially altering the fracture mechanics of calcified tissues and biomaterials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Purpose: In order to limit climate changes, we need to reduce the carbon footprint of human activities, including those due to health systems. We performed an estimation of the carbon footprint of our nuclear medicine department using a methodology developed with the help of a specialized consulting firm., Methods: The estimate of greenhouse gas (GHG) emissions comprises direct and indirect emissions. Direct emissions are due to fuels consumption (by the hospital and by hospital's vehicles), refrigerant leaks and impact of buildings on biomass (land use change). Indirect emissions include upstream and downstream emissions. Upstream emissions are linked to electricity and heating consumption, transport of merchandises, transport of patients and employees, business travels, purchases, and fixed assets. Downstream emissions are due to usage and disposal of manufactured products created by the hospital. Different GHGs (CO 2 , CH 4 , N 2 O…) each have a different global warming potential. To aggregate all GHG emissions, the results were expressed in carbon dioxide equivalent (CO2e)., Results: In 2022, 13,303 diagnostic and therapeutic procedures were performed in our department, for an estimated carbon footprint reaching 772 tons of CO2 equivalent. Transport of people accounts for 67% of total emissions. Purchases are responsible for 14% of total emissions, of which 11.8% are due to radiotracers supply. Energy consumption accounts for 6.9% of total emissions. Imaging devices (2 PET/CT, 2 SPECT/CT and 1 cardiac imaging dedicated CZT camera) account for 5.5% of emissions., Conclusion: Our emissions are mainly due to indirect emission which is a common result in tertiary sector., Competing Interests: Declarations. Ethics approval: approval of our ethics committee was not deemed necessary for this study since no medical, religious or political data was collected. Consent to publish: not applicable. Consent to participate: all individuals involved in this research have voluntarily and freely consented to participate. Competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale and Objectives: This study evaluated the diagnostic performance of 18 F-fluorocholine (FCH) PET/CT as the first-line functional imaging method for preoperative localization of hyperfunctioning parathyroid glands (HPGs) in patients with primary hyperparathyroidism (PHPT)., Materials and Methods: This retrospective single-center study included 80 consecutive patients with PHPT, referred for FCH PET/CT between January 2018 and July 2022, and who subsequently underwent surgery. The diagnostic performance of FCH PET/CT was compared to histological results for per-lesion analysis, and to postoperative resolution of biochemical PHPT for per-patient analysis., Results: 18 F-FCH-PET/CT revealed 95 positive foci in 77/80 patients and was negative in 3/80 patients. Postoperative resolution of HPT was obtained in 67/80 patients (84%). Per-lesion analysis showed 80 true positives, five true negatives, 11 false negatives, and eight false positives. Seven PET-positive foci could not be compared to histology. In a first per-lesion analysis, excluding these seven anomalies, sensitivity and positive predictive value (PPV) of FCH PET/CT were 88% (95% CI: 79-94) and 91% (95% CI: 87-94), respectively. In a second per-lesion analysis considering the seven anomalies as false positives (maximum bias analysis), PPV was 84% (95% CI: 80%-87%). By per-patient analysis, FCH PET/CT correctly identified and located all pathological glands in 56/80 (70%, 95% CI: 59-80) patients., Conclusion: 18 F-Fluorocholine PET/CT appears to be an effective pre-surgical imaging method for localization of hyperfunctioning parathyroid tissue in patients with PHPT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Introduction: Non-invasive ventilation (NIV) is the reference treatment for chronic respiratory failure (CRF) due to impairment of the ventilatory system. Home initiation is increasingly practiced. To better support this ambulatory shift, we aimed to assess the implementation constraints and short-term efficacy according to different aetiologies of CRF., Methods: This retrospective study with cross-sectional and longitudinal analysis included patients initiated with NIV at Angers University Hospital. Patients were separated according to the following aetiologies: obesity hypoventilation syndrome (OHS), chronic obstruction pulmonary disease (COPD), amyotrophic lateral sclerosis (ALS), myopathy and chest wall disease. Implementation constraints were assessed by analysing the variability of NIV settings, the number of masks tried and the duration of hospitalisation. NIV effectiveness was assessed by measuring residual PaCO2 (arterial pressure in CO2), apnoea hypopnea index (AHI flow ) and tidal volume (V T ) (as displayed by the NIV software)., Results: Between October 2020 and May 2022, 102 patients were started with NIV, including a majority of ALS patients. We found a moderate variability in NIV settings (pressure, slope, triggers, etc.) within the different etiological groups, particularly in ALS. On the other hand, ALS patients required more interface trials than other groups and often had unmet efficacy criteria at hospital discharge. Interestingly, longitudinal follow-up showed a progressive improvement in efficacy criteria, particularly in patients who were initially inadequately ventilated., Conclusion: Each aetiological group has specific constraints in the initiation of NIV that should be considered when initiating NIV in the outpatient setting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Trzepizur reports a relationship with AstraZeneca Pharmaceuticals LP that includes: speaking and lecture fees. Trzepizur reports a relationship with ASTEN that includes: travel reimbursement. Trzepizur reports a relationship with Bioprojet that includes: travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Bone is a natural mineral-organic nanocomposite protecting internal organs and allowing mobility. Through the ages, numerous strategies have been developed for repairing bone defects and fixing fractures. Several generations of bone repair biomaterials have been proposed, either based on metals, ceramics, glasses, or polymers, depending on the clinical need, the maturity of technologies, and knowledge of the natural constitution of the bone tissue to be repaired. The global trend in bone implant research is shifting toward osteointegrative, bioactive and possibly stimuli-responsive biomaterials and, where possible, resorbable implants that actively promote the regeneration of natural bone tissue. In this mini-review, the fundamentals of bone healing materials and clinical challenges are summarized and commented on with regard to progressing scientific discoveries. The main types of bone-healing materials are then reviewed, and their specific relevance to the field is reminded, with the citation of reference works. In the final part, we highlight the promise of hybrid organic-inorganic bioactive materials and the ongoing research activities toward the development of multifunctional or stimuli-responsive implants. This contribution is expected to serve as a commented introduction to the ever-progressing field of bone regeneration and highlight trends of future-oriented research.

Since 1998, leuko-reduction is used in France for all platelet concentrates (PCs), apheresis-derived (APCs) and pooled whole blood-derived buffy-coats (BCPCs). Platelet additive solutions (PAS), introduced in 2005, accounted for over 80% of the platelet supply from 2011 to 2017. The Intercept pathogen reduction technology (PR), started in a pilot study in 2007, was generalized in 2018. Between 2007 and 2021, the use of BCPCs increased steadily from 23% to 70% of the supply. Objectives: to analyze the impact of these modifications on adverse transfusion reactions (ATRs), patient management and blood transfusion organization. Results: The overall incidence of ATRs /10 5 PCs is significantly lower with PAS- and PR-PCs as compared to PCs in plasma (PL), with the decreasing hierarchy PL > PAS > PR. PAS- and PR-PCs lead to significantly lower incidences of allergy and alloimmunization to RBC antigens (RC-AI) ATRs. The incidence of bacteria transmission (TTBI) is significantly reduced by 95% with PR-PCs. APC-related ATR incidence is significantly higher than BCPC for allergy (+233%), TTBI (+100%), APTR (+75%), Major-ABO-II (+65%), HLA/HPA-AI (+38%), FNHTR (+22%), and life-threatening ATRs (+106%). A single diagnosis is significantly less associated with APCs: RC-AI (-47%). The generalization of PR-PCs, which exhibit a lower platelet content than PAS- and PL-PCs, is associated with a significant 9% decrease in the ATR incidence per PC, a 13% increase in the number of PCs transfused per patient, and a nonsignificant 3% increase in the ATR incidence per patient. The outdated PCs percentage declined significantly from 3.7% to 1.7%., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose in relation to the submitted review., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: This 65-year-old man suffering from hypercalcemia in a context of hyperparathyroidism treated by calcimimetics was referred to our institution to perform an 18 F-fluorocholine PET/CT in order to localize the pathological parathyroid gland(s). We incidentally discovered a brain metastatic pulmonary large cell neuroendocrine carcinoma in addition to a parathyroid adenoma. This case illustrates the value of FCH PET/CT in hyperparathyroidism workup event under calcimimetic treatment, as well as the potential of FCH PET/CT to reveal occult malignancies., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Nanocrystalline apatites have been intensively studied for decades, not only for their well-known mimesis of bone apatite but also for applicative purposes, whether as biomaterials for skeletal repair or more recently for a variety of nanomedical applications enabled by their peculiar surface characteristics. Particularly, ion-doped apatites are of great interest because the incorporation of foreign ions in the composition of apatite (nano)crystals alters the bulk and surface properties, modifying their ability to interact with the external environment. This is clearly seen in the physiology of bone tissue, whose mineral phase, a low crystallinity apatitic phase, can dynamically exchange ions with cells, thus driving bone metabolism. Taking bone mineral as a model, the present work describes the development of Mg-doped hydroxyapatite nanoparticles, exploiting hydrothermal synthesis to achieve extents of Mg 2+ doping hardly achieved before and using citrate to develop stable apatite colloidal dispersions. Morphological and physicochemical analyses, associated with in-depth investigation of ions populating the apatitic lattice and the nonapatitic surface layer, concurred to demonstrate the cooperative presence of Mg 2+ and citrate ions, affecting the dynamic ion retention/release mechanisms. Achieving high Mg 2+ doping rates and understanding how Mg doping translates into surface activation of apatite-based nanoparticles is expected to foster the design of novel smart and tunable devices, to adsorb and release ionic species and cargo molecules, with potential innovations in the biomedical field or even beyond, as in catalysis or for environmental remediation.

Abstract: Diffuse midline glioma, H3K27-altered, is a relatively new entity, characterized by H3K27M histone mutation. This rare pediatric disease with severe prognosis has recently been identified as a new subtype of diffuse astrocytoma due to major breakthrough in histopathological and molecular characterization of gliomas. We report a case of H3K27-altered diffuse midline glioma in a 30-year-old woman., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Biomarker identification could help in deciphering endometriosis pathophysiology in addition to their use in the development of non invasive diagnostic and prognostic approaches, that are essential to greatly improve patient care. Despite extensive efforts, no single potential biomarker or combination has been clinically validated for endometriosis.Many studies have investigated endometriosis-associated biological markers in specific tissues, but an integrative approach across tissues is lacking. The aim of this review is to propose a comprehensive overview of identified biomarkers based on tissue or biological compartment, while taking into account endometriosis phenotypes (superficial, ovarian or deep, or rASRM stages), menstrual cycle phases, treatments and symptoms.We searched PubMed and Embase databases for articles matching the following criteria: 'endometriosis' present in the title and the associated term 'biomarkers' found as Medical Subject Headings (MeSH) terms or in all fields. We restricted to publications in English and on human populations. Relevant articles published between 01 January 2005 (when endometriosis phenotypes start to be described in papers) and 01 September 2022 were critically analysed and discussed.Four hundred forty seven articles on endometriosis biomarkers that included a control group without endometriosis and provided specific information on endometriosis phenotypes are included in this review. Presence of information or adjustment controlling for menstrual cycle phase, symptoms and treatments is highlighted, and the results are further summarized by biological compartment. The 9 biological compartments studied for endometriosis biomarker research are in order of frequency: peripheral blood, eutopic endometrium, peritoneal fluid, ovaries, urine, menstrual blood, saliva, feces and cervical mucus. Adjustments of results on disease phenotypes, cycle phases, treatments and symptoms are present in 70%, 29%, 3% and 6% of selected articles, respectively. A total of 1107 biomarkers were identified in these biological compartments. Of these, 74 were found in several biological compartments by at least two independent research teams and only 4 (TNF-a, MMP-9, TIMP-1 and miR-451) are detected in at least 3 tissues with cohorts of 30 women or more.Integrative analysis is a crucial step to highlight potential pitfalls behind the lack of success in the search for clinically relevant endometriosis biomarkers, and to illuminate the physiopathology of this disease., (© 2024. The Author(s).)

Background: Hereditary angioedema (HAE) is a potentially life-threatening disorder characterized by recurrent episodes of subcutaneous or submucosal swelling. HAE with normal C1 inhibitor (HAE-nC1-INH) is an underdiagnosed condition. Although the association with genetic variants has been identified for some families, the genetic causes in many patients with HAE-nC1-INH remain unknown. The role of genes associated with bradykinin catabolism is not fully understood., Objective: We sought to investigate the biological parameters and the genes related to kallikrein-kinin system in families with a clinical phenotype of HAE-nC1-INH and presenting with a carboxypeptidase N (CPN) deficiency., Methods: This study includes 4 families presenting with HAE-nC1-INH and CPN deficiency. Patients' clinical records were examined, biological parameters of kallikrein-kinin system were measured, and genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictive algorithms (Human Splicing Finder, Sorting Intolerant From Tolerant, Polymorphism Phenotyping v2, MutationTaster, and ClinPred) were used to classify variants as affecting splicing, as benign to deleterious, or as disease-causing., Results: Patients presented with angioedema and urticaria, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Affected patients displayed low CPN activity-30% to 50% of median value in plasma. We identified 3 variants of the CPN1 gene encoding the catalytic 55-kDa subunit of CPN: c.533G>A, c.582A>G, and c.734C>T. CPN deficiency associated with genetic variants segregated with HAE-nC1-INH symptoms in affected family members., Conclusions: CPN1 gene variants are associated with CPN deficiency and HAE-nC1-INH symptoms in 4 unrelated families. Genetic CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, with synergistic effects in angioedema and urticarial symptoms., Competing Interests: This work was supported by an 10.13039/100017732E-Rare-1 research grant attributed within European FP7 (HAEIII; S. Cichon, coordinator) and a French National Agency for Research grant (grant no. EudraCT #38RC09.023). The promoter for the study was CHU Grenoble Alpes (#2009-A00025-52). Funding was also obtained from the French National Blood Service (Etablissement Français du Sang) La Plaine Saint Denis (grant no. APR2016-64), from KininX SAS, and the National Rare Disease Program from the French Ministry of Health (National Reference Center for Angioedema CREAK). F.P. was recipient of a PhD fellowship from Etablissement Français du Sang (#APR2016-64). Disclosure of potential conflict of interest: F. Parsopoulou, G. Loules, and A. Ghannam received grants as stated in the funding section. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 The Author(s).)

Hybrid organic-inorganic bio-inspired apatite nanoparticles (NPs) are attractive for biomedical applications and especially in nanomedicine. Unfortunately, their applications in nanomedicine are limited by their broad particle size distributions and uncontrolled drug loading due to their multistep synthesis process.  Besides, very few attempts at exposing bioactive peptides on apatite NPs are made. In this work, an original one-pot synthesis of well-defined bioactive hybrid NPs composed of a mineral core of bioinspired apatite surrounded by an organic corona of bioactive peptides is reported. Dual stabilizing-bioactive agents, phosphonated polyethylene glycol-peptide conjugates, are prepared and directly used during apatite precipitation i) to form the organic corona during apatite precipitation, driving the size and shape of resulting hybrid NPs with colloidal stabilization and ii) to expose peptide moieties (RGD or YIGSR sequences) at the NPs periphery in view of conferring additional surface properties to enhance their interaction with cells. Here, the success of this approach is demonstrated, the functionalized NPs are fully characterized by Fourier-transform infrared, Raman, X-ray diffraction, solid and liquid state NMR, transmission electron microscopy, and dynamic light scattering, and their interaction with fibroblast cells is followed, unveiling a synergistic proliferative effect., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

A large amount of research in orthopedic and maxillofacial domains is dedicated to the development of bioactive 3D scaffolds. This includes the search for highly resorbable compounds, capable of triggering cell activity and favoring bone regeneration. Considering the phosphocalcic nature of bone mineral, these aims can be achieved by the choice of amorphous calcium phosphates (ACPs). Because of their metastable property, these compounds are however to-date seldom used in bulk form. In this work, we used a non-conventional "cold sintering" approach based on ultrafast low-pressure RT compaction to successfully consolidate ACP pellets while preserving their amorphous nature (XRD). Complementary spectroscopic analyses (FTIR, Raman, solid-state NMR) and thermal analyses showed that the starting powder underwent slight physicochemical modifications, with a partial loss of water and local change in the HPO 4 2- ion environment. The creation of an open porous structure, which is especially adapted for non-load bearing bone defects, was also observed. Moreover, the pellets obtained exhibited sufficient mechanical resistance allowing for manipulation, surgical placement and eventual cutting/reshaping in the operation room. Three-dimensional porous scaffolds of cold-sintered reactive ACP, fabricated through this low-energy, ultrafast consolidation process, show promise toward the development of highly bioactive and tailorable biomaterials for bone regeneration, also permitting combinations with various thermosensitive drugs.

Context: Old-generation photosensitizers are minimally used in current photodynamic therapy (PDT) because they absorb in the UV/blue/green region of the spectrum where biological tissues are generally highly absorbing. The UV/blue light of Cherenkov Radiation (CR) from nuclear disintegration of beta-emitter radionuclides shows promise as an internal light source to activate these photosensitizers within tissue. Outline of the study: 1) radionuclide choice and Cherenkov Radiation, 2) Photosensitizer choice, synthesis and radiolabeling, 3) CR-induced fluorescence, 4) Verification of ROS formation, 5) CR-induced PDT with either free eosine and free CR emitter, or with radiolabelled eosin., Results: Cherenkov Radiation Energy Transfer (CRET) from therapeutic radionuclides ( 90 Y) and PET imaging radionuclides ( 18 F, 68 Ga) to eosin was shown by spectrofluorimetry and in vitro, and was shown to result in a PDT process. The feasibility of CR-induced PDT (CR-PDT) was demonstrated in vitro on B16F10 murine melanoma cells mixing free eosin (λ abs  = 524 nm, Φ Δ 0.67) with free CR-emitter [ 18 F]-FDG under their respective intrinsic toxicity levels (0.5 mM/8 MBq) and by trapping singlet oxygen with diphenylisobenzofuran (DPBF). An eosin-DOTAGA-chelate conjugate 1 was synthesized and radiometallated with CR-emitter [ 68 Ga] allowed to reach 25 % cell toxicity at 0.125 mM/2 MBq, i.e. below the toxicity threshold of each component measured on controls. Incubation time was carefully examined, especially for CR emitters, in light of its toxicity, and its CR-emitting yield expected to be 3 times as much for 68 Ga than 18 F (considering their β particle energy) per radionuclide decay, while its half-life is about twice as small., Perspective: This study showed that in complete darkness, as it is at depth in tissues, PDT could proceed relying on CR emission from radionuclides only. Interestingly, this study also repurposed PET imaging radionuclides, such as 68 Ga, to trigger a therapeutic event (PDT), albeit in a modest extent. Moreover, although it remains modest, such a PDT approach may be used to achieve additional tumoricidal effect to RIT treatment, where radionuclides, such as 90 Y, are strong CR emitters, i.e. very potent light source for photosensitizer activation., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background : Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in SERPING1 , resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the kallikrein-kinin system (KKS) and its complement. In HAE-C1-INH patients, C1-INH deficiencies affect KKS control, resulting in the development of kallikrein activity in plasma and the subsequent release of bradykinin (BK). While the overwhelming majority of disease-causing SERPING1 variants are dominant, very few recessive variants have been described. We present a large Brazilian HAE-C1-INH family with a recessive form of HAE-C1-INH. Methods: Blood samples of family members were investigated for protein levels of C1-INH, C4, C1q, and C1-INH function. The SERPING1 gene was sequenced. Results: In two severely affected sisters, we identified a homozygous missense variant in SERPING1 (NM_000062.3:c.964G>A;p.Val322Met). Fourteen family members were asymptomatic heterozygous carriers of the variant. Data regarding C1-INH function in the plasma showed that homozygous p.Val322Met strongly impacts C1-INH function to inhibit C1s and kallikrein (PKa). When heterozygously expressed, it affects the C1-INH control of C1s more than that of PKa. Conclusions: These studies of the variant's effects on the structure-function relationship reinforce prior observations suggesting that C1-INH deficiency is a conformational disease.

Bone repair is a major challenge in regenerative medicine, e.g. for large defects. There is a need for bioactive, highly percolating bone substitutes favoring bone ingrowth and tissue healing. Here, a modern 3D printing approach (VAT photopolymerization) was exploited to fabricate hydroxyapatite (HA) scaffolds with a Gyroid-"Triply periodic minimal surface" (TPMS) porous structure (65% porosity, 90.5% HA densification) inspired from trabecular bone. Percolation and absorption capacities were analyzed in gaseous and liquid conditions. Mechanical properties relevant to guided bone regeneration in non-load bearing sites, as for maxillofacial contour reconstruction, were evidenced from 3-point bending tests and macrospherical indentation. Scaffolds were implanted in a clinically-relevant large animal model (sheep femur), over 6 months, enabling thorough analyses at short (4 weeks) and long (26 weeks) time points. In vivo performances were systematically compared to the bovine bone-derived Bio-Oss Ⓡ standard. The local tissue response was examined thoroughly by semi-quantitative histopathology. Results demonstrated the absence of toxicity. Bone healing was assessed by bone dynamics analysis through epifluorescence using various fluorochromes and quantitative histomorphometry. Performant bone regeneration was evidenced with similar overall performances to the control, although the Gyroid biomaterial slightly outperformed Bio-Oss Ⓡ at early healing time in terms of osteointegration and appositional mineralization. This work is considered a pilot study on the in vivo evaluation of TPMS-based 3D porous scaffolds in a large animal model, for an extended period of time, and in comparison to a clinical standard. Our results confirm the relevance of such scaffolds for bone regeneration in view of clinical practice. STATEMENT OF SIGNIFICANCE: Bone repair, e.g. for large bone defects or patients with defective vascularization is still a major challenge. Highly percolating TPMS porous structures have recently emerged, but no in vivo data were reported on a large animal model of clinical relevance and comparing to an international standard. Here, we fabricated TPMS scaffolds of HA, determined their chemical, percolation and mechanical features, and ran an in-depth pilot study in the sheep with a systematic comparison to the Bio-Oss Ⓡ reference. Our results clearly show the high bone-forming capability of such scaffolds, with outcomes even better than Bio-Oss Ⓡ at short implantation time. This preclinical work provides quantitative data validating the relevance of such TMPS porous scaffolds for bone regeneration in view of clinical evaluation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christophe Drouet reports financial support was provided by European Union. David Grossin reports financial support was provided by European Union. Islam Bouakaz reports financial support was provided by European Union. Elisabeth Cobraiville reports financial support was provided by European Union. Gregory Nolens reports financial support was provided by European Union. David Grossin reports financial support was provided by Région Occitanie, France, under the REPERE action No. 18022525. Elisabeth Cobraiville reports financial support was provided by Federation of Wallonia and Brussels. Gregory Nolens reports financial support was provided by Federation of Wallonia and Brussels. Islam Bouakaz reports financial support was provided by Federation of Wallonia and Brussels. Islam Bouakaz, Elisabeth Cobraiville, Gregory Nolens reports a relationship with Cerhum company that includes: employment. This publication follows the ethics of research. The co-authors I.B., E.C. and G.N. mention that the compound MyBone evaluated is commercially available from the Cerhum company, Belgium. This did not alter in any way the scientific data provided which were acquired independently., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Primary objective was to compare the per-patient detection rates (DR) of [ 18 F]DCFPyL versus [ 18 F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT), in patients with first prostate cancer (PCa) biochemical recurrence (BCR). Secondary endpoints included safety and impact on patient management (PM)., Methods: This was a prospective, open label, cross-over, comparative study with randomized treatment administration of [ 18 F]DCFPyL (investigational medicinal product) or [ 18 F]fluoromethylcholine (comparator). Men with rising prostate-specific antigen (PSA) after initial curative therapy were enrolled. [ 18 F]DCFPyL and [ 18 F]fluoromethylcholine PET/CTs were performed within a maximum time interval of 12 days. DR was defined as the percentage of positive PET/CT scans identified by 3 central imaging readers. PM was assessed by comparing the proposed pre-PET/CT treatment with the local treatment", defined after considering both PET/CTs., Results: A total of 205 patients with first BCR after radical prostatectomy (73%; median PSA = 0.46 ng/ml [CI 0.16;27.0]) or radiation therapy (27%; median PSA = 4.23 ng/ml [CI 1.4;98.6]) underwent [ 18 F]DCFPyL- and/or [ 18 F]fluoromethylcholine -PET/CTs, between July and December 2020, at 22 European sites. 201 patients completed the study. The per-patient DR was significantly higher for [ 18 F]DCFPyL- compared to [ 18 F]fluoromethylcholine -PET/CTs (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased with higher PSA values for both tracers (PSA ≤ 0.5 ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0 ng/ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0 ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%) vs. 39/57 (68%) for [ 18 F]DCFPyL- and [ 18 F]fluoromethylcholine -PET/CT, respectively). [ 18 F]DCFPyL PET/CT had an impact on PM in 44% (90/204) of patients versus 29% (58/202) for [ 18 F]fluoromethylcholine. Overall, no drug-related nor serious adverse events were observed., Conclusions: The primary endpoint of this study was achieved, confirming a significantly higher detection rate for [ 18 F]DCFPyL compared to [ 18 F]fluoromethylcholine, in men with first BCR of PCa, across a wide PSA range. [ 18 F]DCFPyL was safe and well tolerated., (© 2023. The Author(s).)

Layered Double Hydroxides (LDHs) are inorganic compounds of relevance to various domains, where their surface reactivity and/or intercalation capacities can be advantageously exploited for the retention/release of ionic and molecular species. In this study, we have explored specifically the applicability in the field of bone regeneration of one LDH composition, denoted "MgFeCO 3 ", of which components are already present in vivo, so as to convey a biocompatibility character. The propensity to be used as a bone substitute depends, however, on their ability to allow the fabrication of 3D constructs able to be implanted in bone sites. In this work, we display two appealing approaches for the processing of MgFeCO 3 LDH particles to prepare ( i ) porous 3D scaffolds by freeze-casting, involving an alginate biopolymeric matrix, and ( ii ) pure MgFeCO 3 LDH monoliths by Spark Plasma Sintering (SPS) at low temperature. We then explored the capacity of such LDH particles or monoliths to interact quantitatively with molecular moieties/drugs in view of their local release. The experimental data were complemented by computational chemistry calculations (Monte Carlo) to examine in more detail the mineral-organic interactions at play. Finally, preliminary in vitro tests on osteoblastic MG63 cells confirmed the high biocompatible character of this LDH composition. It was confirmed that ( i ) thermodynamically metastable LDH could be successfully consolidated into a monolith through SPS, ( ii ) the LDH particles could be incorporated into a polymer matrix through freeze casting, and ( iii ) the LDH in the consolidated monolith could incorporate and release drug molecules in a controlled manner. In other words, our results indicate that the MgFeCO 3 LDH (pyroaurite structure) may be seen as a new promising compound for the setup of bone substitute biomaterials with tailorable drug delivery capacity, including for personalized medicine.

Critical bone defect repair remains a major medical challenge. Developing biocompatible materials with bone-healing ability is a key field of research, and calcium-deficient apatites (CDA) are appealing bioactive candidates. We previously described a method to cover activated carbon cloths (ACC) with CDA or strontium-doped CDA coatings to generate bone patches. Our previous study in rats revealed that apposition of ACC or ACC/CDA patches on cortical bone defects accelerated bone repair in the short term. This study aimed to analyze in the medium term the reconstruction of cortical bone in the presence of ACC/CDA or ACC/10Sr-CDA patches corresponding to 6 at.% of strontium substitution. It also aimed to examine the behavior of these cloths in the medium and long term, in situ and at distance. Our results at day 26 confirm the particular efficacy of strontium-doped patches on bone reconstruction, leading to new thick bone with high bone quality as quantified by Raman microspectroscopy. At 6 months the biocompatibility and complete osteointegration of these carbon cloths and the absence of micrometric carbon debris, either out of the implantation site or within peripheral organs, was confirmed. These results demonstrate that these composite carbon patches are promising biomaterials to accelerate bone reconstruction.

Background: Invasive lobular carcinoma accounts for 10 to 15% of all breast cancers. The first objective of this retrospective study was to assess the diagnostic performance of FDG-PET/CT scanning in women previously treated for invasive lobular carcinoma with suspected first recurrence. The secondary objectives were to evaluate the impact of PET/CT in a change in treatment and its prognostic value on specific survival., Methods: Patients in whom a PET/CT scan was performed from January 2011 to July 2019 in our Cancer Research Center were enrolled. Recurrence was suspected based on clinical symptoms, abnormal findings on conventional imaging, and/or elevated tumor markers. The diagnosis of recurrence was established by the oncologist after integration of all clinical, biological, histological, imaging, and follow-up data. Prognostic factors of recurrence as predicted by PET were determined using univariate logistic regression. KI67, mitotic index, or grade of mitosis were tested. Survival curves were compared using the log-rank test. Sixty-four patients (mean age: 60.3; SD = 12.4 years) were enrolled. The average time from initial diagnosis of the primary tumor to suspicion of recurrence was 5.2 ± 4.1 years. Forty-eight patients (75%) were judged to have recurrence by the oncologist: 7 local and 41 metastatic, with mainly bone ( n = 24), lymph node ( n = 14) and liver ( n = 10) metastases., Results: Sensitivity, specificity, and positive and negative predictive values of PET/CT to predict recurrence were, respectively: 87%, 87%, 95%, and 70%. SUVmax at recurrence sites was generally high (mean: 6.4; SD = 2.9). False negative PET/CT results occurred with local ( n = 2), peritoneal ( n = 2), meningeal ( n = 1), or bladder ( n = 1) recurrences. In 40 patients with available histopathological data from suspected sites of recurrence, 30 PET/CT were true positive. In four patients, primary lung ( n = 1) or gastric ( n = 1) tumors or lymphomas ( n = 2) were found. The detection of a recurrence resulted in a change in treatment in 44/48 patients (92%). No association between recurrence predicted by PET and biological biomarkers was found. Median specific survival appears shorter in patients with metastatic recurrence versus patients with local or no recurrence on PET/CT ( p = 0.067)., Conclusions: FDG-PET/CT is an effective and reliable tool for the detection of invasive lobular carcinoma recurrence, although certain recurrence sites specific to this histological type can impair its diagnostic performance.

Objectives: To investigate the performance of cranial PET/CT for the diagnosis of GCA., Methods: All patients with a suspected diagnosis of GCA were prospectively enrolled in this study and had a digital PET/CT with evaluation of cranial arteries if they had not started glucocorticoids >72 h previously. The diagnosis of GCA was retained after at least 6 months of follow-up if no other diagnosis was considered by the clinician and the patient went into remission after at least 6 consecutive months of treatment. Cranial PET/CT was considered positive if at least one arterial segment showed hypermetabolism similar to or greater than liver uptake., Results: For cranial PET/CT, sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were 73.3%, 97.2%, 91.7% and 89.7%, respectively. For extracranial PET/CT, diagnostic performance was lower (Se = 66.7%, Sp = 80.6%, PPV = 58.8%, NPV = 85.3%). The combination of cranial and extracranial PET/CT improved overall sensitivity (Se = 80%) and NPV (NPV = 90.3%) while decreasing overall specificity (Sp = 77.8%) and PPV (PPV = 60%)., Conclusion: Cranial PET/CT can be easily combined with extracranial PET/CT with a limited increase in examination time. Combined cranial and extracranial PET/CT showed very high diagnostic accuracy for the diagnosis of GCA., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05246540., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Epoxy-amine systems are ubiquitous in the field of industrial thermosetting polymers, often used in a moist atmosphere. In addition, previous studies showed amine-metal interactions through the formation of an interphase, with the formation of surface complexes that may involve the formation of water molecules. However, to date, the impact of water on an epoxy/amine-metal interphase has not been specifically addressed. In this work, we examined for the first time the role of this potential fourth component by way of a dual experimental/computational approach. The effect of water on the glass-transition temperature of the obtained polymers was quantified. The in situ formation of a DETA-Al-water interphase was followed by mixing calorimetry. The DETA-water interaction was highly exothermic, and the underlying mechanism was discussed on the basis of DETA hydration, which was confirmed by density functional theory (DFT) and Monte Carlo simulations. Taking into account the pre-existing interaction between diethylenetriamine (DETA) molecules allowed us to model all experimental data. Comparison of experimental and calculated IR spectra contributed to validate the simulation parameters used. Our findings indicate that the presence of water may noticeably affect epoxy-amine-based systems. Mixing calorimetry and computational modeling appear as particularly adapted tools for the comprehension of such complex systems.

Biomimetic nanocrystalline apatites analogous to bone mineral can be prepared using soft chemistry. Due to their high similarity to bone apatite, as opposed to stoichiometric hydroxyapatite for example, they now represent an appealing class of compounds to produce bioactive ceramics for which drug delivery and ion exchange abilities have been described extensively. However, immersion in aqueous media of dried non-carbonated biomimetic apatite crystals may generate an acidification event, which is often disregarded and not been clarified to-date. Yet, this acidification process could limit their further development if it is not understood and overcome if necessary. This may, for example, alter biological test outcomes, during their evaluation as bone repair materials, due to potentially deleterious effects of the acidic environment on cells, especially in in vitro static conditions. In this study, we explore the origins of this acidification phenomenon based on complementary experimental data and we point out the central role of the hydrated ionic layer present on apatite nanocrystals. We then propose a practical strategy to circumvent this acidification effect using an adequate post-precipitation equilibration step that was optimized. Using this enutralization protocol, we then showed the possibility of performing (micro)biological assessments on such compounds and provide an illustration with the examples of post-equilibrated Cu 2+ - and Ag + -doped nanocrystalline apatites. We demonstrate their non-cytotoxicity to osteoblast cells and their antibacterial features as tested versus five major pathogens involved in bone infections, therefore pointing to their relevance in the field of antibacterial bone substitutes. The preliminary in vivo implantation of a relevant sample in a rat's calvarial defect confirmed its biocompatibility and the absence of adverse reaction. Understanding and eliminating this technical barrier should help promoting biomimetic apatites as a genuine new class of biomaterial-producing compounds for bone regeneration applications, e.g., with antibacterial features, far from being solely considered as "laboratory curiosities".

Biomimetic apatites exhibit a high reactivity allowing ion substitutions to modulate their in vivo response. We developed a novel approach combining several bioactive ions in a spatially controlled way in view of subsequent releases to address the sequence of events occurring after implantation, including potential microorganisms' colonization. Innovative micron-sized core-shell particles were designed with an external shell enriched with an antibacterial ion and an internal core substituted with a pro-angiogenic or osteogenic ion. After developing the proof of concept, two ions were particularly considered, Ag + in the outer shell and Cu 2+ in the inner core. In vitro evaluations confirmed the cytocompatibility through Ag-/Cu-substituting and the antibacterial properties provided by Ag + . Then, these multifunctional "smart" particles were embedded in a polymeric matrix by freeze-casting to prepare 3D porous scaffolds for bone engineering. This approach envisions the development of a new generation of scaffolds with tailored sequential properties for optimal bone regeneration.

Human kallikrein-kinin system (KKS) is a proteolytic cascade with two serine-protease zymogen couples (Factor XII and prekallikrein (PK) and their activated forms, FXIIa, PKa, respectively), releasing bradykinin by cleavage of native high-molecular-weight kininogen (nHK) into cleaved HK. For KKS investigation in human plasma, this cascade is usually triggered on ice eventually by mixing with purified proteins. It has been established that purified FXIIa, PK, and nHK required a fixed order and timing for mixing protein on ice to ensure reproducibility of testing, we investigated the activation kinetics of both enzymes. The activation process of this in vitro minimal reconstitution of KKS was studied by progress curve analysis, in condition of high enzyme/substrate ratio and by using on natural rather than peptide substrates. FXIIa and PKa were found five-times less active on ice than at 37°C: kcat = 0.133 ± 0.034 and 0.0119 ± 0.0027 s-1, KM = 672 ± 150 and 115 ± 24 nM, respectively. The progress curve analysis of our in vitro KKS reconstitutions differed from a Michaelis-Menten mathematical simulation by a faster initial rate and a slower late rate. These two features were also observed ex vivo by using dextran sulfate-activated plasma and could reinforce the hypothesis of a maximal local effect (bradykinin release) and a minimal systemic consequence (PK preservation) in KKS activation process. Analyzing the complete curve of cold KKS activation would provide valuable information for ex vivo investigation of KKS in samples from patients presenting with hereditary angioedema and other inflammatory conditions., (© 2022 The Author(s).)

Biphasic macroporous Hydroxyapatite/β-Tricalcium Phosphate (HA/β-TCP) scaffolds (BCPs) are widely used for bone repair. However, the high-temperature HA and β-TCP phases exhibit limited bioactivity (low solubility of HA, restricted surface area, low ion release). Strategies were developed to coat such BCPs with biomimetic apatite to enhance bioactivity. However, this can be associated with poor adhesion, and metastable solutions may prove difficult to handle at the industrial scale. Alternative strategies are thus desirable to generate a highly bioactive surface on commercial BCPs. In this work, we developed an innovative "coating from" approach for BCP surface remodeling via hydrothermal treatment under supercritical CO 2 , used as a reversible pH modifier and with industrial scalability. Based on a set of complementary tools including FEG-SEM, solid state NMR and ion exchange tests, we demonstrate the remodeling of macroporous BCP surface with the occurrence of dissolution-reprecipitation phenomena involving biomimetic CaP phases. The newly precipitated compounds are identified as bone-like nanocrystalline apatite and octacalcium phosphate (OCP), both known for their high bioactivity character, favoring bone healing. We also explored the effects of key process parameters, and showed the possibility to dope the remodeled BCPs with antibacterial Cu 2+ ions to convey additional functionality to the scaffolds, which was confirmed by in vitro tests. This new process could enhance the bioactivity of commercial BCP scaffolds via a simple and biocompatible approach.

Bone infections are a key health challenge with dramatic consequences for affected patients. In dentistry, periodontitis is a medically compromised condition for efficient dental care and bone grafting, the success of which depends on whether the surgical site is infected or not. Present treatments involve antibiotics associated with massive bacterial resistance effects, urging for the development of alternative antibacterial strategies. In this work, we established a safe-by-design bone substitute approach by combining bone-like apatite to peroxide ions close to natural in vivo oxygenated species aimed at fighting pathogens. In parallel, bone-like apatites doped with Ag + or co-doped Ag + /peroxide were also prepared for comparative purposes. The compounds were thoroughly characterized by chemical titrations, FTIR, XRD, SEM, and EDX analyses. All doped apatites demonstrated significant antibacterial properties toward four major pathogenic bacteria involved in periodontitis and bone infection, namely Porphyromonas gingivalis ( P. gingivalis ), Aggregatibacter actinomycetemcomitans ( A. actinomycetemcomitans ), Fusobacterium nucleatum ( F. nucleatum ), and S. aureus . By way of complementary tests to assess protein adsorption, osteoblast cell adhesion, viability and IC 50 values, the samples were also shown to be highly biocompatible. In particular, peroxidated apatite was the safest material tested, with the lowest IC 50 value toward osteoblast cells. We then demonstrated the possibility to associate such doped apatites with two biocompatible polymers, namely gelatin and poly(lactic-co-glycolic) acid PLGA, to prepare, respectively, composite 2D membranes and 3D scaffolds. The spatial distribution of the apatite particles and polymers was scrutinized by SEM and µCT analyses, and their relevance to the field of bone regeneration was underlined. Such bio-inspired antibacterial apatite compounds, whether pure or associated with (bio)polymers are thus promising candidates in dentistry and orthopedics while providing an alternative to antibiotherapy.

Background: Cadmium-zinc-telluride (CZT) SPECT/CT cameras with large field of view offer a higher sensitivity than conventional Anger cameras. This prospective study aimed to determine the equivalence between a conventional protocol and a reduced acquisition time protocol for 201-Thallium myocardial perfusion imaging (MPI) using a whole-body CZT SPECT camera., Methods and Results: Stress MPI was obtained for 103 consecutive patients on a DISCOVERY-CZT camera. Images were anonymized and post-processed to simulate a 25% (D75 dataset) and 50% (D50 dataset) decrease in total recorded counts. Concerning the number of segments displaying a tracer uptake < 70% of maximum intensity per patient, equivalence was demonstrated for both count-reduced datasets with a good inter-observer agreement (between 0.90 and 0.88). When comparing the full-vs-D75 datasets and full-vs-D50 datasets, mean difference was 0.06 segment (CI95: [- 0.15;0.27], P < 0.001) and 0.518 segment (CI95: [0.28;0.76], P < 0.001) respectively. Inter-observer agreement was also moderate to good concerning the number of pathological segments (between 0.6 and 0.7) and excellent for functional parameters., Conclusion: Whole-body CZT SPECT/CT cameras allow to reduce 201-Thallium MPI injected activity or acquisition time by 50% with an equivalence in the number of segments displaying a tracer uptake < 70% of maximum intensity and with a good inter-observer agreement., (© 2021. American Society of Nuclear Cardiology.)

The SuperCam instrument, onboard the Perseverance rover (Mars 2020 mission) is designed to perform remote analysis on the Martian surface employing several spectroscopic techniques such as Laser Induced Breakdown Spectroscopy (LIBS), Time-Resolved Raman (TRR), Time-Resolved Fluorescence (TRF) and Visible and Infrared (VISIR) reflectance. In addition, SuperCam also acquires high-resolution images using a color remote micro-imager (RMI) as well as sounds with its microphone. SuperCam has three main subsystems, the Mast Unit (MU) where the laser for chemical analysis and collection optics are housed, the Body Unit (BU) where the different spectrometers are located inside the rover, and the SuperCam Calibration Target (SCCT) located on the rover's deck to facilitate calibration tests at similar ambient conditions as the analyzed samples. To perform adequate calibrations on Mars, the 22 mineral samples included in the complex SCCT assembly must have a very homogeneous distribution of major and minor elements. The analysis and verification of such homogeneity for the 5-6 replicates of the samples included in the SCCT has been the aim of this work. To verify the physic-chemical homogeneity of the calibration targets, micro Energy Dispersive X-ray Fluorescence (EDXRF) imaging was first used on the whole surface of the targets, then the relative abundances of the detected elements were computed on 20 randomly distributed areas of 100 × 100 μm. For those targets showing a positive Raman response, micro-Raman spectroscopy imaging was performed on the whole surface of the targets at a resolution of 100 × 100 μm. The %RSD values (percent of relative standard deviation of mean values) for the major elements measured with EDXRF were compared with similar values obtained by two independent LIBS set-ups at spot sizes of 300 μm in diameter. The statistical analysis showed which elements were homogeneously distributed in the 22 mineral targets of the SCCT, providing their uncertainty values for further calibration. Moreover, nine of the 22 targets showed a good Raman response and their mineral distributions were also studied. Those targets can be also used for calibration purposes of the Raman part of SuperCam using the wavenumbers of their main Raman bands proposed in this work., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: A. Cochet et L. Darley déclarent n’avoir aucun lien d’intérêts. C. Drouet déclare avoir été pris en charge par GE Healthcare à l’occasion de déplacements pour congrès.

Few data are currently available on hypersensitivity transfusion reactions (HTRs) after exposure to fresh frozen plasma (FFP). Between 2000 and 2018, three different FFP production strategies have been used in France, leading to the concomitant use of different types of FFP. The objective of this study was to describe the rate of FFP-related HTRs and to assess the relative risk of each type of FFP. HTR following FFP transfusion between 2000 and 2018 were retrospectively extracted from the national hemovigilance database of the French National Agency for Medicines and Health Products Safety (ANSM). Temporal evolution of the incidence of reactions was modeled using logistic regression. During the study period, the overall rate of FFP-related HTRs was 52.0 (95% CI 50.2-53.9) reactions per 100,000 units of FFP issued. The rate of FFP-related HTRs progressively increased over the study period, from 28.7 (95% CI 22.8-36.0) in 2000 to 88.9 (78.8-100.3) reactions per 100,000 units of FFP issued in 2018 (OR 1.08 [1.07 - 1.09], P < .001), whereas the rate of other types of adverse transfusion reactions (ATRs) decreased. Between 2000 and 2014, its period of use, Solvent-Detergent-treated Apheresis FFP (SD-APH) was associated with the lowest risk of HTR. Our results indicate that although the rate of HTRs to FFP is low in France, the risk of having such a reaction has steadily increased between 2000 and 2018. A declarative bias is unlikely as the rate of other type of FFP-related ATRs decreased over the same period. The risk of HTRs to FFP is suggested to differ according to the processing of the FFP with a lower risk for SD-APH., Competing Interests: Conflict of interest The authors have no conflict of interest to disclose in relation to the submitted review., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene ( n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein-kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure-function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs ( n = 25). Exonic variants ( n = 6) can affect exon splicing. Rare deep-intron variants ( n = 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance ( n = 74). This category includes some homozygous ( n = 10) or compound heterozygous variants ( n = 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a de novo variant. Situations with paternal or maternal disomy have been recorded ( n = 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy., Competing Interests: AGh was employed by KininX SAS. FP and AGe were employed by CeMIA SA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Drouet, López-Lera, Ghannam, López-Trascasa, Cichon, Ponard, Parsopoulou, Grombirikova, Freiberger, Rijavec, Veronez, Pesquero and Germenis.)

A biomaterial that is both bioactive and capable of controlled drug release is highly attractive for bone regeneration. In previous works, we demonstrated the possibility of combining activated carbon fiber cloth (ACC) and biomimetic apatite (such as calcium-deficient hydroxyapatite (CDA)) to develop an efficient material for bone regeneration. The aim to use the adsorption properties of an activated carbon/biomimetic apatite composite to synthetize a biomaterial to be used as a controlled drug release system after implantation. The adsorption and desorption of tetracycline and aspirin were first investigated in the ACC and CDA components and then on ACC/CDA composite. The results showed that drug adsorption and release are dependent on the adsorbent material and the drug polarity/hydrophilicity, leading to two distinct modes of drug adsorption and release. Consequently, a double adsorption approach was successfully performed, leading to a multifunctional and innovative ACC-aspirin/CDA-tetracycline implantable biomaterial. In a second step, in vitro tests emphasized a better affinity of the drug (tetracycline or aspirin)-loaded ACC/CDA materials towards human primary osteoblast viability and proliferation. Then, in vivo experiments on a large cortical bone defect in rats was carried out to test biocompatibility and bone regeneration ability. Data clearly highlighted a significant acceleration of bone reconstruction in the presence of the ACC/CDA patch. The ability of the aspirin-loaded ACC/CDA material to release the drug in situ for improving bone healing was also underlined, as a proof of concept. This work highlights the possibility of bone patches with controlled (multi)drug release features being used for bone tissue repair.

Aims: Osteosarcoma represents the second most common cause of death in children and young adults. No biomaterial allowing local drug delivery has been specifically developed. However, a biocompatible bioactive implantable material could prevent some amputations, and the local release of an antitumor agent could limit risks of relapse and metastasis. Methods: We propose a proof of concept of a self-setting paste combining amorphous calcium phosphate and doxorubicin-loaded particles of bone-like carbonated nanocrystalline apatite, as a means of local release. Results: The cement formulation and doping, first with folic acid and then with doxorubicin, was successful. Its physicochemistry was scrutinized. Preliminary in vivo data on an invasive osteosarcoma rat model suggest a limiting effect on metastatic events in the lungs without signs of toxicity.

Autologous indium-111 labelled platelets can be used for kinetic studies in patients with autoimmune thrombocytopenic purpura [AITP]. The objective of this study was to evaluate some biological and clinical factors influencing the labeling efficiency., Methods: We studied incubation media (Plasma media [MP] or dry media [MS]), platelet concentration [NP], mean platelet volume [VPM], hemoglobin level and pathology associated with AITP., Results: This was a retrospective study of 93 platelets labelling (43 in MS and 50 in MP), 38 primary AITP (41%) and 55 secondary AITP (59%). The labeling efficiency was 72% (78% in MS versus 53% in MP; p < 0.0001). The labeling efficiency was correlated with VPM (p = 0.0004), NP (p = 0.03), hemoglobin level (p = 0.037) and type of AITP (p = 0.0036). The incubation medium, hemoglobin level and type of the AITP have an independent predictive value on the labeling efficiency., Conclusion: These data confirm the influence of the incubation medium on the labeling efficiency and identify two other predictive criteria, hemoglobin level and type of AITP.

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is caused by mutations affecting the SERPING1 gene. Adult patients (≥ 18 years old) diagnosed with C1-INH-HAE were clustered according to a modified SERPING1 gene mutation classification [5]. Demographic, clinical, and laboratory data were studied. Published manuscripts on the genotype/phenotype relationship were reviewed. Eighty-eight patients participated in the study, with 78 having a classifiable mutation. We compared the data in the 3 largest groups: class 0 only (n = 32), class II only (n = 18), class III only (n = 22). Antigenic C4 and C1 inhibitors were higher in class II (p = 0.008 and p = 0.02, respectively), and facial attacks in the last 6 months were more frequent in class III (p = 0.04)). All the other differences were non-significant. Twelve manuscripts on phenotype/genotype correlation were found: missense mutations in SERPING1 gene were associated with delay in disease onset and lower severity score in some studies, whereas the CC F12-C46T/C polymorphism produced earlier disease onset. Our study shows minimal differences regarding clinical phenotype in patients with class 0, II, and III SERPING1 gene mutations, with a tendency to class III having a more severe phenotype. The study should be performed in a larger sample to confirm if they are significant.We propose that larger multicenter, international studies are performed, comparing different SERPING1 gene mutation classifications, combining polymorphisms in other involved genes (kallikrein-kinin system, regulation of vasculature, plasminogen activation) and using different variables and clinical scores to assess C1-INH-HAE disease activity and/or severity in order to study possible genotype/phenotype relationships., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Driven by flexibility, precision, repeatability and eco-friendliness, laser-based technologies have attracted great interest to engineer or to analyze materials in various fields including energy, environment, biology and medicine. A major advantage of laser processing relies on the ability to directly structure matter at different scales and to prepare novel materials with unique physical and chemical properties. It is also a contact-free approach that makes it possible to work in inert or reactive liquid or gaseous environment. This leads today to a unique opportunity for designing, fabricating and even analyzing novel complex bio-systems. To illustrate this potential, in this paper, we gather our recent research on four types of laser-based methods relevant for nano-/micro-scale applications. First, we present and discuss pulsed laser ablation in liquid, exploited today for synthetizing ultraclean "bare" nanoparticles attractive for medicine and tissue engineering applications. Second, we discuss robust methods for rapid surface and bulk machining (subtractive manufacturing) at different scales by laser ablation. Among them, the microsphere-assisted laser surface engineering is detailed for its appropriateness to design structured substrates with hierarchically periodic patterns at nano-/micro-scale without chemical treatments. Third, we address the laser-induced forward transfer, a technology based on direct laser printing, to transfer and assemble a multitude of materials (additive structuring), including biological moiety without alteration of functionality. Finally, the fourth method is about chemical analysis: we present the potential of laser-induced breakdown spectroscopy, providing a unique tool for contact-free and space-resolved elemental analysis of organic materials. Overall, we present and discuss the prospect and complementarity of emerging reliable laser technologies, to address challenges in materials' preparation relevant for the development of innovative multi-scale and multi-material platforms for bio-applications.

The aims of this study were to assess the dependence of glomerular filtration rate (GFR) on age and gender and to produce reference data for the interpretation of 51 Cr-EDTA GFR measurements in adults., Methods: This was a retrospective study of 120 live kidney donors (75 females, 45 males). GFR was evaluated from 51 Cr-EDTA plasma clearance using blood samples taken at 3, 4 and 5 hours. The slope-intercept GFR was corrected for body surface area using the Dubois & Dubois and for the fast exponential using the Brochner-Mortensen equation. Scatter plot of DFG against age in live kidney donors was plotted and the 98% range limits have been defined., Results: The median GFR obtained for kidney donors was 88 mL/min/1.73 m 2 [68-130]. No significant difference with gender was found. 51 Cr-EDTA clearance was strongly correlated with patient age (r = - 0.62, P < 0,0001). GFR decreased by approximately 8 mL/min/1.73 m 2 per decade. Based on these results, a nomogram for GFR is presented., Conclusion: The interpretation of GFR requires age-adjusted normal values. These standards need not be adjusted to the patient's sex or BMI.

Background: 18 F-fluorocholine positron emission tomography/computed tomography (F-choline PET/CT) is considered a cornerstone in the staging and restaging of patients with prostate cancer (PCa). The aim of this study was to retrospectively assess unusual uptakes in patients who underwent a F-choline PET/CT for the initial staging or for the restaging of a relapsing PCa., Methods: Three hundred and sixty-eight PCa patients were staged or restaged using F-choline PET/CT. Unusual uptakes were defined as uptakes occurring outside the usual paths of diffusion of PCa or as uptake in bone with a clear morphological evidence of nonmetastatic lesion., Results: We found unusual uptakes in 47/368 patients (12.8%). Among them, 41/47 presented with benign F-choline uptake, usually within lymph nodes, due to inflammatory processes (22/47). Other benign processes were found in: thyroid (3/47), adrenal gland (3/47), brain (2/47), liver (1/47), bowel (3/47), frontal sinus (1/47), lungs (4/47), parotid gland (1/47) and bone (1/47). The six remaining patients presented with a second cancer, including lymphoma (1/47), non-small cell lung cancer (4/47) and neuroendocrine tumor (1/47)., Conclusions: unusual uptakes on F-choline PET/CT are quite frequent and should be explored since they may correspond to non-PCa., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-19-981). Dr. AC serves as an unpaid editorial board member of Quantitative Imaging in Medicine and Surgery. The other authors have no conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Most treatments of skin pathologies involve local administration of active agents. One issue can however be the partial transcutaneous diffusion of the drug to blood circulation, leading to undesirable effects. In this work, the original use of submicron mineral particles based on bio-inspired calcium phosphate apatite was explored for the first time as drug carriers for favoring topical delivery. The permeation of a model drug across synthetic and biological membranes was investigated in both static and dynamic conditions. Our data show that adsorption of the drug on the apatite particles surface drastically limits its permeation, with lower effective diffusion coefficients (P eff ) and smaller total released amounts. The retention of the apatite colloidal particles on porcine ear skin explants surface was demonstrated by combining histological observations and Raman confocal microscopy. All results converge to show that association of the drug to apatite particles favors skin surface effects. These findings point to the relevance of mineral-based particles as drug carriers for local delivery to the skin, and open the way to novel applications of bio-inspired apatites in dermatology. STATEMENT OF SIGNIFICANCE: Calcium phosphates (CaP) are major biomaterials in orthopedics and dentistry. Their resemblance to bone mineral allows new applications beyond bone repair, e.g. in nanomedicine. In 2018, a 14-page detailed review (M. Epple, Acta Biomaterialia 77 (2018) 1-14) provided clear facts in favor of the non-toxicity of nanosized CaP as an answer to discussions from EU and US study groups, thus clarifying the path to novel applications of nano CaP. In the present paper, bio-inspired apatite nanoparticles are used for the first time as drug carriers for dermatology for drastically limiting drug transcutaneous permeation and retaining a topical effect. We demonstrate this proof of concept via permeation cell tests, histology, Raman microscopy and photoluminescence after application on porcine ear skin., (Copyright © 2020. Published by Elsevier Ltd.)

This 37-year-old woman was diagnosed with breast cancer during pregnancy. After multidisciplinary meeting, she was referred to our department for an FDG PET/CT for staging, and chemotherapy with weekly infusion of paclitaxel was initiated before childbirth. We estimated the fetal dose from the PET/CT procedure, and our results show that, if deemed necessary, this examination can reasonably be performed during pregnancy. The patient gave birth vaginally at term to an apparently healthy girl.

The purpose of this work was to compare the measured red-cell volume (RCV) using sodium pertechnétate [RCV- 99m Tc] compared to the reference technique using sodium radiochromate [RCV- 51 Cr] and to assess the influence of technetium-99 elution on the RCV- 99m Tc value. Ten patients had simultaneous measurements of RCV- 99m Tc and RCV- 51 Cr. Elution of Tc-99m from red blood cells was 2.9% and led to an average overestimation of RCV- 99m Tc of 3.7%. The introduction of individual tracer elution rates in the RCV- 99m Tc calculation corrects this overestimation.

Background: Among labile blood products, platelet concentrates (PCs) are the leading cause of hypersensitivity transfusion reactions (HTRs). These reactions often lead to interruption of PC transfusion and can result in a prolonged transfusion process leading to significant morbidity and use of premedication and close monitoring for patients with a history of allergic transfusion reactions. The French hemovigilance database is one of the largest standardized databases providing information on HTRs following administration of labile blood products. In this study, we analyzed this database to assess the relative risk of HTR for each type of PC., Study Design and Methods: HTRs following PC transfusion were retrospectively extracted from the e-Fit Hemovigilance database of the French National Agency for Medicines and Health Products Safety (ANSM). Frequencies were calculated using the number of specific PCs transfused., Results: Between 2008 and 2014, the overall estimated incidence of HTRs following PC administration was calculated at 232 HTRs per 100,000 PCs transfused. The rate of HTRs was significantly higher with apheresis PC (337/100,000) than with buffy-coat PC (94/100,000). Platelets in additive solutions (PAS) were associated with a significantly lower frequency of HTRs when compared with PCs in native plasma. Amotosalen/UVA- PCs (APCs and BCPCs) which are always in PAS in France, exhibited the lowest frequency of HTRs when compared with their corresponding PCs in native plasma or in PAS (p < 10 -7 in all comparisons)., Conclusion: Our results showed that the type of PC and its processing may have an impact on the risk of HTR., (© 2019 AABB.)

Hereditary angioedema (HAE) is becoming much more genetically complex than was initially considered. Thus, the role of HAE genetics is expanding beyond research laboratories, and the genotyping of subjects suffering from HAE has become diagnostically indispensable in clinical practice. The synthesis and interpretation of the clinical and biochemical analyses to facilitate appropriate genetic test selection has thus also become significantly more complex. With this in mind, an international multidisciplinary group of 14 experts in HAE genetics and disease management was convened in October 2018. The objective was to develop clear, actionable, evidence- and consensus-based statements aiming to facilitate the communication between physicians treating patients with HAE and clinical geneticists, and thus promote the effective use of genetics in the management of the disease. Eleven consensus statements were generated, encompassing considerations regarding the clinical indications for genotyping patients with angioedema, the methods of detection of HAE-causative variants, the variant pathogenicity curation, the genotyping of patients with HAE in the clinic, and genetic counseling. These statements are intended both to guide clinicians and to serve as a framework for future educational and further genetic testing developments as the field continues to evolve rapidly., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

In the field of bone regeneration, some clinical conditions require highly-resorbable, reactive bone substitutes to rapidly initiate tissue neo-formation. In this view, Amorphous Calcium Phosphates (ACP) appear as well suited bioceramics taking into account their high metastability. However, the metastability also leads to difficulties of sintering without transformation into crystalline compounds. In this work, various calcium phosphate samples (co)doped with carbonate (CO 3 ) and magnesium ions were synthesized by the double decomposition method in alkaline media using ammonium and potassium hydroxide solutions. The obtained amorphous powders possess an exceptionally-high carbonate content up to 18.3 wt%. Spark Plasma Sintering (SPS) at very low temperature (150 °C) was then utilized to consolidate initial powders with the view to preserve their amorphous character. The influence of the introduction of different apatite growth inhibitors such as carbonate (CO 2- ) and magnesium ions were synthesized by the double decomposition method in alkaline media using ammonium and potassium hydroxide solutions. The obtained amorphous powders possess an exceptionally-high carbonate content up to 18.3 wt%. Spark Plasma Sintering (SPS) at very low temperature (150 °C) was then utilized to consolidate initial powders with the view to preserve their amorphous character. The influence of the introduction of different apatite growth inhibitors such as carbonate (CO 3 2- ) and magnesium ions was studied. XRD and FTIR analyses revealed that sintered ceramics generally consisted in highly carbonated low-crystallinity apatites, which are expected to have higher solubility than conventional apatite-based systems. However, most interestingly, modulation of the doping conditions allowed us to retain, for the first time, the amorphous character of ACP powders after SPS. Such consolidated ACP compounds may now be considered as a new family of bioceramics with high metastability allowing the fast release of bioactive ions upon resorption.